Post-operative treatment of prostate and mammary carcinomas using gonadotropin releasing hormone (or “GnRH”, also referred to as luteinizing hormone releasing hormone, or “LHRH” in the literature) agonists is a standard treatment; cf. Gonzalez-Barcena et al., 1994, The Prostate 24, 84-92; Emons and Schally, 1994, Human Reproduction Update 9, No. 7, 1364-1379. The GnRH receptor is a well-known target in tumor therapy.
The amino acid sequence of human GnRH has been characterized as pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2. A second form, or isoform of GnRH, referred to as “GnRH-II”, is widely conserved among vertebrates, including humans, and has been shown to exhibit a high binding affinity for the GnRH receptor both in primate and human (Davidson, J. S., McArdle, C. A., Davies, P. et al. (1996) Asn109 of the gonadotropin-releasing hormone receptor is a critical determinant of potency for agonists containing C-terminal glycamide. J. Biol. Chem., 271, 15510-15514; Sherwood, N. M., Lovejoy, D. A. and Coe, I. R. (1993) Origin of mammalian gonadotropin-releasing hormones. Endocr. Rev., 14, 241-254. C-terminal glycamide. J. Biol. Chem., 271, 15510-15514; Lescheid, D. W., Terasawa, E., Abler, L. A. et al. (1997). Another form of GnRH that has characteristics of chicken GnRH-II is present in the primate brain Endocrinology, 138, 5618-5629, and has the sequence of pGlu-His-Trp-Ser-His-Gly-Trp-Tyr-Pro-Gly-NH2, which differs from the mammalian GnRH sequence at the fifth, seventh and eighth amino acids (White, R. B., Eisen, J. A., Kasten, T. L. et al. (1998) Second gene for gonadotropin-releasing hormone in humans. Proc. Natl. Acad. Sci. USA, 95, 305-309.).
Thus, in various steroid hormone (i.e. sexual hormone) dependent malignant tumors, such as mammary carcinoma, prostate carcinoma, ovarian carcinoma, and endometrial carcinoma, a double-effect has been observed in clinical studies upon treatment with GnRH agonists, namely: 1) an indirect anti-proliferative activity through the uncoupling of the positive endocrine (estrogenous or androgenous) effect on tumor growth; and 2) a direct anti-proliferative activity by an unknown mechanism through the action of GnRH receptors on the tumor tissue itself; cf. Emons and Schally, 1994, Human Reproduction Update 9, 1364-1379.
This observed indirect effect due to steroid hormone dependence has been known for decades concerning prostate and the mammary carcinoma; cf. Gonzalez-Barcena et al., 1994, The Prostate 24, 84-92; Jonat et al., 1995, European Journal of Cancer 31A, 137-142.
The direct anti-proliferative effect of GnRH agonists and GnRH antagonists on e.g. prostate carcinomas, mammary carcinomas, and ovarian carcinomas has been confirmed by clinical studies. Several of the GnRH agonists employed in these treatments that have a direct anti-proliferative effect are known by the following trademarks of these medicaments, which are approved in Germany, for example: ZOLADEX® (goserelin acetate implant), ZOLADEX 10.8® (goserelin acetate implant), ZOLADEX GYN® (goserelin acetate implant), PROFACT®-DEPOT, PROFACT® PRO INJECTIONE/NASAL, SYNARELA®, ENANTONE MONATS-DEPOT®, UNO-ENANTONE®, ENANTONE GYN MONATS-DEPOT®, TRENANTONE®, SUPRECUR®, CARCINIL®, or DECAPEPTYL® 0.5 mg/0.1 mg, DECAPEPTYL® DEPOT, DECAPEPTYL® GYN as well as DECAPEPTYL® DIAGNOSTIK.
Research using cell cultures has revealed that GnRH receptors are present on human primary liver cell carcinomas and pancreatic adenocarcinomas. In addition, the beginning of a biochemical metabolic reaction with respect to cleavage of GnRH between tyrosine 5 and glycine 6 in rat glioma and rat neuroblastoma has been described; cf. Tao et al., 1991, Neuropeptides 20, 125-131. Ligand binding of GnRH to the GnRH receptor and its signal transduction, however, takes place in a different way, namely at the eighth amino acid of GnRH, arginine, and this exclusively occurs in the case of an intact conformation of the GnRH molecule and its amino acid side chains (Naor, Z., Schacham, Sh., Harris, D., Seger, R., and Reiss, N., 1995, Signal Transduction of the Gonadotropin Releasing Hormone (GnRH) Receptor: Cross-Talk of Calcium, Protein Kinase C (PKC), and Arachidonic Acid. Cellular and Molecular Neurobiology, vol. 15, 527-545). In a normal rat adenohypophysis, where GnRH receptors reside, GnRH leads to an increased cAMP production, however, it is still unclear whether this is a direct or an indirect effect (i.e. a paracrine interaction). For the functioning of the GnRH receptor in rat, including secretion of LH as well as an increased production of LH stimulated by GnRH, the biochemical metabolism of GnRH, e.g. by means of cAMP, plays only an indirect role (Abdilnour, G., and Bourne, G. A., 1995, Adenosine 3′,5′-cyclic mono-phosphate and the self-priming effect of gonadotropin-releasing hormone. Molecular and Cellular Endocrinology, 107, 1-7). Naturally, GnRH receptors have been localized on human gonadotropin producing pituitary adenomas (Alexander, J. P., and Klibanski, A., Gonadotropin-releasing Hormone Receptor mRNA Expression by Human Pituitary Tumors In Vitro, 1994, Journal of Clinical Investigation, 93, 2332-2339).
In the case of glioma and other malignant tumors of ectodermal origin, such as malignant melanoma and, in particular in the case of diffusely growing tumors in the nervous system or in the case of metastases (formation of disseminations, for example, in other organs such as oat-cell carcinoma in the lung), life expectancy is not optimistic. The same is true for Kaposi sarcoma. “Glioma” refers to predominantly brain-localized true tumors of the central nervous system (CNS) originating in the neuroglia, i.e. from the covering and supporting tissue of the nervous system that is derived from ectoderm. These gliomas are present in various stages of differentiation. Subtypes of glioma include spongioblastoma, oligodendroglioma, astrocytoma, glioblastoma, and retinoblastoma. In particular, the Glioblastoma multiforme (GBM) type of brain tumor is characterized by rapid growth and an extremely high rate of recurrence (i.e., a high percentage of patients experience brain tumor recurrence following surgical macroscopic excision).
Reactive gliosis is a space occupying lesion in the central nervous system (CNS), especially in the brain and the spinal cord, and is synonymous with “nonspecific gliosis”, and comprises reactive astrocytes, or reactive neuroglia cells, which are GnRH-receptor positive. These lesions, called “gliotic lesions” or “gliosis lesions”, occur mostly simultaneously at multiple sites within the central nervous system. “Reactive astrocytes” are astrocytes that become reactive in response to many CNS pathologies, including stroke, trauma, growth of a tumor or neurodegenerative disease. (Neuroscience, Volume 54, Issue 1, May 1993, Pages 15-36 Eddleston, M. and Mucke L. Molecular profile of reactive astrocytes—Implications for their role in neurological disease.) Reactive astrocytes occur prominently in response to all forms of central nervous-system injury or disease. The sources of reactive astrocytes appeared to be derived from proliferation, hypertrophy and hyperplasia (The Histochemical Journal, Volume 14, Number 2, March 1982. Ultrastructural Study of Enzymes in Reactive Astrocytes: Clarification of Astrocytic Activity. S. Y. A. Al-Ali and N. Robinson.). The gliosis lesions are considered a gliotic “scar”. The process of astrocyte activation, identical for all forms of reactive astrocytes, results in nonspecific gliosis. (Trends in Neurosciences, Volume 17, Issue 4, 1994, Pages 138-142 Michael K. McMillian, Linda That, J-S. Hong, James P. O'Callaghan, Keith R. Pennypacker. Brain injury in a dish: a model for reactive gliosis). The diagnosis of “gliosis” is a pathological diagnosis typically made following resection of the gliotic lesion, or at least part of that lesion, e.g. by means of a brain biopsy (Waltregny A. et al. Contribution of stereotactic brain biopsies to the diagnosis of pre-senile dementia. Stereotactic. Funct. Neurosurg. (1990); 54-55: 409-412).
Malignant melanoma occurring in the CNS, primary or as metastasis, as well as malignant melanoma that primarily occurs in the skin, and/or malignant melanoma that disseminates (metastasizes) further in the skin and/or in other body organs, belong to a group of nervous system derived tumors; cf. Shamamian et al., 1994, Cancer Immunol. Immunother. 39, 73-83; Florenes et al., 1994, Cancer Research, 54, 354-356. Malignant melanomas are derived from the neuroectoderm, an embryonic layer. Burg et al., 1997, Deutsches Ärzteblatt 94, 890-895, describe a tumor growth inhibiting effect of Tamoxifen for malignant melanoma. Furthermore, glioblastoma and malignant melanoma have several tumor markers in common; cf. Shamamian et al., 1994, Cancer Immunol. Immunother. 39, 73-83; Florenes et al., 1994, Cancer Research 54, 354-356. In the case of metastases, the prognosis is quite poor; cf. Burg et al., 1997, Deutsches Ärzteblatt 94, 890-895.
Tumors originating in brain and/or nervous system and/or the meninges further comprise the neuroblastoma and the medullablastoma which, in their entirety, have been classified as the so-called primitive neuroectodermal tumors, abbreviated as PNET. These tumors further include the pinealoma, which originates in pineal body parenchyma and/or primordial germ cells in the pineal body region or the brain median. Moreover, the pineal body is associated with the origin of craniopharyngeoma (a tumor producing β-HCG or LH-like glycoprotein, respectively; cf. Tachibana et al., 1994, J. of Neurosurgery 80, 79-84), which is considered to be an ectodermal tumor and originates in the front/upper face of the pituitary.
For both craniopharyngeoma and meningeoma, which is considered to be a benign tumor originating in arachnoidal cover cells and often adhering firmly to the inner surface of the meninges (dura mater), the presence of progesterone receptors and estrogen receptors have been described. Furthermore, androgen receptors have also been established in the case of meningeoma. In clinical studies using anti-progesterone medicaments, tumor-shrinking effects have been observed.
Up to now, the investigation of alternative tumor therapies (different forms of chemotherapy, radiotherapy, etc.) in numerous clinical studies has failed to provide a substantial improvement of the prognosis for those tumors originating in the brain and/or nervous system and/or the meninges. At present, the standard therapy in the case of Glioblastoma multiforme consists of a complete as possible surgical excision of the tumor followed by conventional radiotherapy. Under this standard therapy protocol, the statistically reported mean survival time is 9-13 months, with individual variation and a slightly better prognosis for younger patients having been observed.
About 30% of patients with recurrent Glioblastoma multiforme show either a constant size or shrinking, respectively, of the inoperable residual brain tumor under sustained high-dosages of Tamoxifen, an anti-estrogen preparation. This tumor-inhibiting effect in glioblastoma treatment has not been attributed to its anti-estrogenic effect, but instead to its inhibition of protein kinase C (an intracellular signal mediator); cf. Puchner et al., Zentralblatt für Neurochirurgie, Supplement 1996, 47. Jahrestagung Deutsche Gesellschaft für Neurochirurgie, page 44; Pollack et al., 1995, The Efficacy of Tamoxifen as an anti-proliferative Agent in vitro for Benign and Malignant Pediatric Glial Tumors, Pediatr. Neurosurgery 22, 281-288). Moreover, Tamoxifen is known to increase the sensitivity of tumor cells for platinum-containing therapeutics as well as for radiotherapy.
For Glioblastoma multiforme (WHO grade IV astrocytoma) and for glioma with a lower grade of malignancy (WHO grade II-IV astrocytoma), steroid hormone receptors have been observed in a smaller percentage of the cases (cf. Paoletti et al., 1990, J. Neurosurgery, Characteristics and biological role of steroid hormone receptors in neuroepithelial tumors, 73, 736-742). Until now, an indirect anti-proliferative effect in the case of Glioblastoma multiforme and glioma grade II-IV has been observed in clinical studies in only about 30% of the cases via a response of the tumor to Tamoxifen administration (an anti-estrogen preparation).
Recently, several relatively reasonable new developments in Glioblastoma multiforme therapy have been described, although the prognosis quod vitam for patients with Glioblastoma multiforme remains poor due to the extremely high recurrence rate, despite the therapy regimens tried and tested so far, and also due to the lack of a specific therapy and early diagnosis. The oat-cell carcinoma, another malignant tumor, is frequently found in lungs and is also derived from neural cells (Tecimer et al Arch. Pathol. Lab. Med., 124, 520-525, 2000).